Topics. What are Prediction Factors? Seizure type Etiologies Frequency of seizures Response to first AED Genetic?

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1 Early Recognition and Management of Refractory Epilepsy Topics How to predict who developed refractory epilepsy Associate Professor Somsak Tiamkao Division of Neurology, Department of Medicine Faculty of Medicine, Khon Kaen University Khon Kaen, 17 April,8 How to manage patient with refractory epilepsy Thailand s guideline of management Clinical trial of Lamictal Common Epilepsy Treatment Path Pharmacoresistance Surgery Natural History of Treated Epilepsy Unanswered Questions First monotherapy New AEDs,Polytherapy dom Alternative monotherapy Seizurefreedom Seizurefreedom Outcome with respect to treatment course Response to the first drug, second drug etc When to use polytherapy What are useful combinations When is drug resistant epilepsy recognised Can refractory epilepsy be identified early What are Prediction Factors Seizure type Etiologies Frequency of seizures Response to first AED Genetic Early Identification of Refractory Epilepsy Glasgow Study Prospective follow up at AED initiation 525 consecutive patients untreated at referral 47 never treated previously Median age 29 years (range 993) Median follow up 5 years (215.6) 1 year terminal seizurefree: 63% Kwan P and Brodie MJ. N Engl J Med ;342:

2 Newly Diagnosed Epilepsy One year terminal remission First drug monotherapy 47% Second drug monotherapy 13% Third drug monotherapy 1% Duotherapy 3% Total seizure free 64% Outcome and Classification Glasgow Study n Seizure free Idiopathic 1 74% * Symptomatic 15 57% Cryptogenic % *p=.4; idiopathic vs. symptomatic cryptogenic Kwan P and Brodie MJ. N Engl J Med ;342:3149 Kwan P and Brodie MJ. N Engl J Med ;342:3149 Outcome and Etiology Glasgow Study Newly Diagnosed Epilepsy Probability of seizurefreedom Percentage of Patients 8 6 *P<.5 * Cortical dysplasia Hippocampal sclerosis Cortical atrophy Cerebral gliosis Cerebral tumour AVM Cerebral infarct Cryptogenic Percentage of patients or more Successive antiepileptic drug regimens Stephen LJ, Kwan P, Brodie MJ. Epilepsia 1;42: Kwan P and Brodie MJ, Neurology 2;58(Suppl 5):S2S8 First Drug Failure and Outcome Response to first drug trial predicts outcome in childhood temporal lobe epilepsy Dlugos DJ, Sammel MD, Strom BL, Farrar JT Neurology 1;57: Retrospective study 1 patients aged 1 to 18 years Outcome at 2 years after onset of TLE Only failure of first AED trial predicted poor outcome Positive predictive value.89 Negative predictive value.95 Dlugos DJ et al, Neurology 1;57:

3 % Patients Outcome after Failure on First AED 5 11% 41% 55% 7% Ineffective (n=113) Intolerable Side Effects (n=69) Idiosyncratic Reaction (n=29) Others (n=37) Figure on top of bar represents percentage seizurefree Seizure free Uncontrolled χ 2 = 57, P <.1 Initial AED Response and Outcome Poor response to AED at 6 12 months predicts poor longterm outcome: Sillanpää M et al, 1998 Arts WFM et al, 1999 Hans L et al, 1 Kwan P and Brodie MJ. N Engl J Med ;342:3149 Outcome and Pretreatment Seizure Number Glasgow Study % Patients 5 12 (n=11) 35 (n=19) Kwan P and Brodie MJ. N Engl J Med ;342: % 27% % 37% 51% 61 (n=73) 11 (n=57) > (n=185) Number of pretreatment seizures Figure on top of bar represents percentage uncontrolled uncontrolled Seizure free Uncontrolled χ 2 = 32.7, P <.1 Outcome and Initial Seizure Density National GP Epilepsy Study % in remission Years from 6 month postindex seizure MacDonald BK et al, Ann Neurol ;48: year remission 5year remission Index seizure only 2 seizures 5 seizures 1 seizures Pretreatment seizure number High number predicts poor outcome: Reynolds et al, 1989 Camfield et al, 1993 Arts et al, 1999 Kwan and Brodie, Association of multidrug resistance in epilepsy with a polymorphism in the drugtransporter gene ABCB1 Siddiqui A, Kerb R, Weale ME et al. N Engl J Med 3;348:

4 MDR1 and Epilepsy Pglycoprotein encoded by MDR1 (or ABCB1) Pumps drugs out of cells Expressed in cerebral capillary endothelium (BBB) Overexpressed in patients with refractory epilepsy Induced by experimental seizures Certain AEDs are substrates of Pgp Hypothesis: Overexpression of MDR1 causes drug resistance by reducing AED access to the epileptogenic lesion CordonCardo et al, 1989; Tishler DM et al, 1995; Kwan P et al, 2; Sills GJ, Kwan P et al, 3 Conclusion: Poor Prognostic Factors Symptomatic/lesional epilepsy (MTS) Poor response to the first antiepileptic drug High pretreatment seizure number/frequency Others: Poor response to AED at 6 12 months Generalised epileptiform activity on EEG Generalised tonicclonic seizures Genetic predisposition Good Outcome Low seizure no./freq. brain lesion Respond to 1 st drug Moderate doses in most (Genetic polymorphism) Newly Diagnosed Epilepsy Twopopulation Theory 6% % Difficulttotreat de novo High seizure frequency Structural brain lesion Failed 2 AEDs (Genetic polymorphism) Management Paradigm Newly Diagnosed Epilepsy 1st Drug 2nd Drug 47% 13% % Difficulttotreat Brodie MJ and Kwan P, Neurology 2;58(8 Suppl 5):S28. Rational polytherapy Brodie MJ and Kwan P, CNS Drugs 1;15:112 Surgical assessment Management Paradigm Monotherapy vs. Duotherapy Failed 1 st AED due to lack of efficacy Newly Diagnosed Epilepsy % patients Poor Prognostic Group 1st Drug 2nd Drug % Difficulttotreat 47% 13% % 26% 62% 26% 57% 17% Intolerable AE Inadequate control Rational duotherapy Surgical assessment Duotherapy Kwan P and Brodie MJ, Seizure ;9:4648 Alternative monotherapy 4

5 Monotherapy vs. Duotherapy Doubleblind RCT 13 newly diagnosed untreated epilepsy patients Equal drug loads of CBZ or CBZVPA 12month followup difference in neurotoxicity score difference in seizure frequency during follow up Withdrawal due to adverse events Duotherapy 14% Monotherapy 22% Deckers CLP et al, Epilepsia 1;42: % patients staying on treatment Monotherapy vs. Duotherapy Retention Rate 5 Deckers CLP et al, Epilepsia 1;42: CBZVPA (n=67) CBZ alone (n=63) 3 Time (days) P=.16 SeizureFree* Rates with Monotherapy and Polytherapy monotherapy 1st AED 5% Previously Untreated Patients (n = 78) monotherapy 2nd AED 7% monotherapy 3rd AED 1% Mohanraj R, Brodie MJ. Epilepsy Behav. 5;6: monotherapy 4th 6th AED t seizurefree 35% polytherapy 5% 1% * Defined as no seizures for >1 year with unchanged AED dosage Expert Opinion for the Treatment of Epilepsy (5): Overall Treatment Strategies STEP 1:Monotherapy STEP 2:Second monotherapy STEP 3:Additional trials of monotherapy or combination of 2 AEDs STEP 4:Second combination of 2 AEDs or evaluation for surgery STEP 5:Multiple options including additional combinations of 2 AEDs, combination of 3 AEDs, VNS, ketogenic diet Karceski S, et al. Epilepsy Behav. 5;7:S1 S64. Rational Duotherapy Mechanistic Approach Rational Duotherapy Mechanistic Approach Combinations Mechanisms Seizure type % patients seizurefree % Sodium blocker multiple actions P<.5 7% Other combinations PHT/PB Na blocker/gaba GTCS, Partialonset PHT/VPA Na blocker/multiple GTCS PHT/CLZ Na blocker/gaba GTCS CBZ/VPA Na blocker/multiple GTCS, Partialonset CBZ/VGB Na blocker/gaba Partialonset CBZ/TPM Na blocker/multiple GTCS LTG/VPA Na blocker/multiple GTCS, Partialonset LTG/TPM Na blocker/multiple GTCS, Partialonset PB/TPM GABA/multiple GTCS VPA/ESM Multiple/TCa 2 Absence Kwan P and Brodie MJ, Seizure ;9:4648 Deckers CLP et al, Epilepsia ;41:

6 Management of Epilepsy Goals of therapy 1 Control seizures Minimize adverse events Improve quality of life Important considerations Comorbidities 2,3 Psychosocial needs 4 1. Dam M. In: Engel J Jr, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. Vol 2. Philadelphia, Pa: LippincottRaven; 1997: Boro A, Haut S. Epilepsy Behav. 3;4:S2S Karceski S, et al. Epilepsy Behav. 5;7:S1S Schachter SC. Epilepsy Behav. ;1:1127. Drug Phenobarbital Phenytoin Carbamazepine Valproate Clobazam Clonazepam Kwan P and Brodie MJ, Lancet 1;357:21622 Neuropsychological Effects Established AEDs Cognitive Behavioural Neuropsychological Effects Newer AEDs Selected Epilepsy Comorbidities Lamotrigine Vigabatrin Gabapentin Topiramate Tiagabine Oxcarbazepine Zonisamide Levetiracetam Kwan P and Brodie MJ, Lancet 1;357:21622 Cognitive () Behavioural ( ) Avoided by slow titration Behavioral or mood disturbances Cognitive impairment Reproductive endocrine dysfunction Boro A, Haut S. Medical comorbidities in the treatment of epilepsy. Epilepsy Behav. 3;4(suppl 2):S2S12. Epilepsy Comorbidities: Psychiatric Psychiatric Disorder Rate, % Anxiety disorders 1 19% to 66% Major depression 1 % to 57% Bipolar symptoms 2 12% Psychosis 1 Interictal psychosis 9% Postictal psychosis 6% 1. Boro A, Haut S. Epilepsy Behav. 3;4(suppl 2):S2S Ettinger AB, et al. Neurology 5;65:5355. Epilepsy Comorbidities: Cognitive Impairment Causes 13 Underlying disease Seizures Treatment Types Memory loss Memory loss is common in epilepsy 2 Especially in temporal lobe epilepsy 2,4 Speech or behavior effects 3 1. Meador KJ. Neurology. 2;58(suppl 5):S21S Glowinski H. J Nerv Ment Dis. 1973;157: Aldenkamp AP, et al. Epilepsia. 3;44(suppl 4): Jokeit H, et al. Neurology. 1;57:

7 Reproductive Endocrine Dysfunction Polycystic Ovary Syndrome (PCOS) Ovulatory dysfunction and hyperandrogenism in absence of adrenal or thyroid disease More common in female patients with epilepsy than in the general population Associated with health risks, including insulin resistance, type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease Duncan S. Epilepsia, 1, 42: Genton P, et al. Epilepsia. 1;42: Herzog AG, Schachter SC. Epilepsia. 1;42: AEDs and risk of fractures Odd ratio Carbamazepine 1.88 Valproate 1.57 Phenobarbital 1.84 Phenytoin 1.67 Lamotrigine.58 Polytherapy 2.82 Pathogenesis of bone disorder 1. Accelerated vit D metabolism 2. Hyperparathyroidism 3. Altered vit K metabolism 4. Low calcitonin, calcium absorption 5. Low exercise 6. Fall 7. Hormonal changes What do we want to MODEL and then PREVENT Identify and Prophylactically Treat Patients at Risk Reduce Prevent Development Frequency Initiating Event Critical modulators Structural / Functional changes Seizures EPILEPSY Refractory Epilepsy Prevent Emergence Neurobehavioral changes, Cognitive impairment 7

8 Surgical assessment Poor Prognostic Group Management Paradigm Newly Diagnosed Epilepsy 1st Drug 2nd Drug % Difficulttotreat 47% 13% New AEDs ก ก :Thai CPG ก ก 1. ก ก ก (difficulttotreat) 2. ก ก ก (refractory) Rational duotherapy Surgical assessment ก ก ก 1. ก ก 2. ก 3. ก ก ก Medical refractory epilepsy ก ก CBZ, PHT, VPA, PB monotherapy 2 ก 2 1 ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก ก 8

9 Antiepileptic Drugs in the United States phenobarbital LAMICTAL gabapentin felbamate valproate carbamazepine ethosuximide phenytoin oxcarbazepine zonisamide levetiracetam topiramate tiagabine pregabalin Selecting an Antiepileptic Drug Choose the antiepileptic drug most suited to the individual patient 1 Seizure/epilepsy type Side effects Patient profile (eg, sex, age) Ease of use Cost Balance efficacy, tolerability, and safety 1,2 Epilepsy may be a lifelong diagnosis 1 1. Dam M. In: Engel J Jr, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. Vol 2. Philadelphia, Pa: LippincottRaven; 1997: French JA, et al. Neurology. 4;62: Treatment of new onset epilepsy Drugs Gabapentin Lamotrigine Topiramate Tiagabine Oxcarbazepine Levetiracetam Newly diagnosed MonoRx Partial/Mixed Newly diagnosed Absence NEUROLOGY 4;62: Zonisamide NEUROLOGY 4;62: Type of seizure Partial Second generalize Tonic clonic Absence Myoclonic Lennox Gastaut Infantile spasm FBM VGB TGB GBP OXC LTG TPM LEV PGB * Hitiris N, Brodie MJ. Curr Opin Neurol 6;19:1758 ZNS Milestones for LAMICTAL 1981: Epilepsy studies initiated 199: First marketing approval for epilepsy granted (Ireland) 1994: FDA approval in US as adjunctive therapy for partial seizures in adults with epilepsy 1998: FDA approval for generalized seizures of LennoxGastaut syndrome (adjunctive therapy in pediatric and adult patients) and conversion to monotherapy for adults with partial seizures taking carbamazepine, phenytoin, phenobarbital, or primidone as the single antiepileptic drug 9

10 Milestones for LAMICTAL 2:First global approval for use in bipolar disorder 3: FDA approval for adjunctive therapy for partial seizures in pediatric patients 2 years of age FDA approval for maintenance treatment of adults with bipolar I disorder to delay the time to occurrence of mood episodes in adult patients treated for acute mood episodes with standard therapy 4: FDA approval for conversion to monotherapy for adults with partial seizures taking valproate 6:FDA approval for adjunctive therapy for primary generalized tonicclonic seizures in adults and pediatric patients 2 years of age LAMICTAL: Adjunctive Therapy for PGTC Seizures in Patients 2 Years of Age LAMICTAL as Adjunctive Therapy for PGTC Seizures: Primary Objective To assess the efficacy and tolerability of LAMICTAL as adjunctive therapy in pediatric and adult patients with PGTC seizures LAMICTAL as Adjunctive Therapy for PGTC Seizures: Key Inclusion Criteria Patients 2 years of age and 13 kg Diagnosis of epilepsy with PGTC seizures (with or without other idiopathic generalized seizure types) 1 PGTC seizure in the 8 consecutive weeks prior to baseline 3 PGTC seizures during 8week baseline phase* Receiving 1 or 2 AEDs at a stable dose for 4 weeks Patients with partial seizures were excluded on the basis of seizure history and screening EEG * Baseline assessment of PGTC seizure frequency was prospective, historical, or a combination of prospective and historical. Biton V, et al. Neurology. 5;65: Biton V, et al. Neurology. 5;65: LAMICTAL as Adjunctive Therapy for PGTC Seizures: Study Design Screen Baseline Phase* Escalation Phase 2 wks 8 wks 212 yrs = 12 wks >12 yrs = 7 wks LAMICTAL Randomization Placebo Maintenance Phase 12 wks LAMICTAL Placebo LAMICTAL as Adjunctive Therapy for PGTC Seizures: Primary Endpoint Results Median % Decrease 8 6 Median % Decrease From Baseline in PGTC Seizures LAMICTAL Existing Therapy (n=58) Placebo Existing Therapy (n=59) P= P= P= Concurrent AEDs (stable number and dose) * Baseline assessment of PGTC seizure frequency was prospective, historical, or a combination of prospective and historical. * Primary endpoint. Escalation Maintenance Esc Maint* Biton V, et al. Neurology. 5;65: Biton V, et al. Neurology. 5;65: Adapted with permission. 1

11 LAMICTAL as Adjunctive Therapy for PGTC Seizures: Secondary Endpoint Results Median % Decrease Median % Decrease From Baseline in All Generalized Seizures 8 6 LAMICTAL Existing Therapy (n=58) Placebo Existing Therapy (n=59) P= P= P= Escalation Maintenance Esc Maint * In Escalation and Maintenance phases combined. Biton V, et al. Neurology. 5;65: Adapted with permission. Data on file, GlaxoSmithKline. Biton V, et al. Neurology. 5;65: LAMICTAL as Adjunctive Therapy for PGTC Seizures: Overall Conclusions Significant benefits of adjunctive LAMICTAL versus placebo: Median percent reductions in PGTC seizures: 67% for LAMICTAL vs 34% for placebo* Median percent reductions in all generalized seizures: 47% for LAMICTAL vs 16% for placebo* Percent of patients with 5% reduction in PGTC seizure frequency: 64% for LAMICTAL vs 39% for placebo* Efficacy was similar across age groups Favorable tolerability profile in adults, adolescents, and children LAMICTAL as Adjunctive Therapy for Partial Seizures in Pediatric Patients: Efficacy LAMICTAL: Adjunctive Therapy for Partial Seizures in Pediatric Patients 2 Years of Age Patients with 5% reduction in seizure frequency (%) 8 6 Patients (%) with 5% reduction from baseline in seizure frequency* LAMICTAL Placebo 57% 53% n = 45% n = 42% P <.1 n = 98 P =.4 P =.15 P =.23 n = 98 3% 25% 26% 16% n = 11 All partial seizure frequency Weeks *Protocolspecified secondary analyses. Duchowny M, et al. Neurology. 1999;53: n = 11 n = 46 Secondarily generalized seizure frequency* Weeks n = 46 LAMICTAL: Adjunctive Therapy for Generalized Seizures of LennoxGastaut Syndrome in Patients 2 Years of Age LAMICTAL as Adjunctive Therapy for Generalized Seizures of LGS: Efficacy Patients Treated with LAMICTAL Experienced a Significantly Greater Reduction in Seizure Frequency Than Those Treated with Placebo Reduction in seizure frequency (%) 34% 36% LAMICTAL 32% Placebo 3 n = 6 n = 75 n = P =.2 9% n = 89 All major motor seizures P =.1 9% n = 89 Drop attacks* P =.3 1% n = 64 Tonicclonic seizures* Median Reduction from Baseline in Weekly Seizures During Treatment Weeks 1 16 *A protocolspecified secondary analysis Motte J, et al. N Engl J Med. 1997;337:

12 LAMICTAL: Conversion from a Single EIAED * in Adults LAMICTAL: Conversion to Monotherapy with LAMICTAL from Carbamazepine or Phenytoin as the Single AED in Patients 16 Years of Age with Partial Seizures Carbamazepine or phenytoin LAMICTAL or valproate Randomized, doubleblind, doubledummy study to evaluate efficacy and safety of LAMICTAL 5 mg as monotherapy 156 outpatients (13 73 years of age) with partial seizures uncontrolled with carbamazepine or phenytoin as monotherapy Valproate mg/day was given as an active control to provide some degree of seizure protection *Enzymeinducing antiepileptic drug Data cannot be interpreted as showing superiority of LAMICTAL over an adequate dose of valproate. Gilliam F, et al. Neurology. 1998;51: Adapted with permission. Proportion remaining in study LAMICTAL: Conversion from a Single EIAED in Adults KaplanMeier curve of proportion of patients remaining in trial after addition of LAMICTAL or valproate P =.1 LAMICTAL 5 mg/day vs valproate mg/day LAMICTAL (n = 5) Valproate (n = 64) Weeks on study drug Data cannot be interpreted as showing superiority of LAMICTAL over an adequate dose of valproate. Gilliam F, et al. Neurology. 1998;51: Adapted with permission. Median days patients remained in trial = 168 days Median days patients remained in trial = 57 days Cognitive Effects of Adjunctive LAMICTAL for Pediatric* and Adult Patients With Epilepsy: Results significant clinical impairment on tested cognitive domains 1,2 Tested cognitive domains included Memory Attention and concentration Cognitive and motor speed Language * 7 years of age. 1. Blum D, et al. Neurology. 6;67:6. 2. Pressler RM, et al. Neurology. 6;66: Effects of Other AEDs on Serum Concentration of Lamotrigine Effects of LAMICTAL on Serum Concentration of Other AEDs Lamotrigine concentration Carbamazepine Effect of concomitant medication Phenytoin Valproate Oxcarbazepine Levetiracetam Felbamate Gabapentin Pregabalin Topiramate Zonisamide Carbamazepine concentration Phenytoin concentration Valproate concentration Oxcarbazepine concentration Levetiracetam concentration Felbamate concentration Gabapentin concentration Pregabalin concentration Topiramate concentration Zonisamide concentration Effect of concomitant LAMICTAL * t assessed t assessed t assessed *Approximately 25% decrease in healthy volunteers; however, no change in plasma concentration in adult or pediatric patients has been observed in controlled trials. Slight increase not expected to be clinically relevant. 12

13 taking Valproate* Dosing of LAMICTAL in Patients >12 Years of Age With Epilepsy Weeks 1 & 2 Weeks 3 & 4 Weeks 5 onwards to maintenance 25 mg every other day 25 mg every day Increase by 25 to 5 mg/day every 1 to 2 weeks not taking CBZ, PHT, PB, Primidone, or Rifampin and not taking Valproate* Weeks 5 onwards Weeks 1 & 2 Weeks 3 & 4 to maintenance Usual maintenance dose 25 mg every day 5 mg/day Increase by 5 mg/day every 1 to 2 weeks Usual maintenance dose to mg/day (1 or 2 divided doses) 225 to 375 mg/day (in 2 divided doses) Use of LAMICTAL in Special Populations taking CBZ, PHT, PB, Primidone, or Rifampin and not taking Valproate* Weeks 5 onwards Weeks 1 & 2 Weeks 3 & 4 to maintenance Usual maintenance dose 5 mg/day mg/day in 2 divided doses Increase by mg/day every 1 to 2 weeks 3 to 5 mg/day (in 2 divided doses) Doses above target dose are not recommended To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded *Valproate has been shown to decrease the apparent clearance of LAMICTAL. CBZ, PHT, PB, primidone, and rifampin have been shown to increase the apparent clearance of LAMICTAL. Pregnancy June 6 GlaxoSmithKline voluntarily issued a Dear HCP Letter to inform healthcare professionals about emerging data from the rth American AED Pregnancy Registry, which suggests an association between LAMICTAL and an increased risk of nonsyndromic oral clefts September 6 Information Sheets for patients and healthcare professionals regarding this information were posted on the FDA s Web site The Information Sheets provide no new information regarding the oral cleft pregnancy registry findings To view the Information Sheets go to: LAMICTAL is Pregnancy Category C Odd ratio is more less than other AEDs Epilepsy in Older Adults: Special Treatment Considerations Seizure type and etiology Pharmacokinetic changes Slower drug metabolism Decreased protein binding Decreased renal clearance Reduced compliance Memory loss Visual impairment Comorbid illnesses Concomitant medications Drug interactions Sabers A, Gram L. Drugs. ;6: Guideline of Epilepsy: Thailand New AEDs 1. Partial, GTC seizure LTG,GBP, TPM, VGB, TGB, LEV, OXC 2. Infantile spasms VGB Guideline of Epilepsy: Thailand New AEDs 3. LennoxGastaut syndrome LTG, TPM, FBM, ZNS 4. Monotherapy LTG, TPM, GBP, OXC 13

14 Type of seizure FBM VGB TGB GBP OXC LTG TPM LEV PGB ZNS Partial Second generalize Tonic clonic Absence Myoclonic * Lennox Gastaut Infantile spasm Summary of AAN evidencebased guidelines level A or B recommendation AED Partial adjunctive adult Gabapentin Lamotrigine Levetiracetam Partial Monotherapy Primary generalized Symptomatic generalized Pediatric partial Hitiris N, Brodie MJ. Curr Opin Neurol 6;19: Good Quality of Life Thank you for your attention 14